It is well known that women suffer disproportionately from anxiety and anxiety-related diseases and are at a higher risk for cardiovascular disease (Cloitre et al., 2004;Pigott;Jackson, 2008). While a role for estrogen in promoting anxiety-related disorders has been suggested (Altemus, 2006), the effects of estrogen, and the body's response to changes in estrogen levels remain unclear. The purpose of this proposal is to investigate the relationship between estrogen and the neuropeptide oxytocin (OT), in particular their relationship in mediating anxiety-like behavior. Our preliminary data indicate that estrogen administration significantly increases anxiety-like behavior and the autonomic stress response in female prairie voles. Additionally, we have found that estrogen administration significantly increases OT immunoreactivity in the paraventricular nucleus of the hypothalamus (PVN). OT is primarily thought to have anxiolytic effects (Neumann, 2008);therefore, we hypothesize that OT is increased in estrogen-treated animals, at least in part, to mitigate the anxiogenic effects of estrogen administration. The site of action of OT released from cells in the PVN is likely the central nucleus of the amygdala (CeA), a region known to be involved in anxiety-like behavior (Jasnow et al, 2006;Davis, 2000). This proposal will investigate the hypothesis that OT in the CeA mitigates the anxiogenic effects of estrogen administration. In Aim 1, ovariectomized female prairie voles, previously implanted with radiotelemetric devices for monitoring autonomics, will be implanted with either empty or estradiol benzoate (EB) containing silastic tubing. A dose-response to EB will be determined. After two weeks, animals will be tested for anxiety-like behavior (open field anxiety measure, light-dark box, and elevated plus maze) and response to a social stressor (resident-intruder test). Autonomics will be measured continuously. Aims 2 and 3 will investigate the role of OT signaling in the CeA on the effects of EB. Animals will be implanted with bilateral cannulae directed at the CeA, and infused with either OT (Aim 2) or OTA (Aim 3) to determine if enhancing or inhibiting OT in the CeA modulates the anxiogenic and stress response enhancing effects of EB. The experiments described here will offer important information about the ability of OT to modulate estrogen-induced anxiety. Basic research regarding the nature of the relationship between estrogen and OT can be used to inform the development of better methods for understanding, preventing and treating anxiety-related diseases.